Type 2 Diabetes and hypertension are major health care crises affecting over 18 and 70 million Americans respectively. To date, pharmacologic treatment of many type 2 diabetic patients require separate agents for treating hyperglycemia and hypertension. S43126, an Imidazoline compound, has the potential to treat both diabetes and hypertension simultaneously. Previous results have shown that Imidazoline compounds that are agonists at the I1 -imidazoline receptor act centrally to lower blood pressure and also play a role in the treatment of insulin resistance and diabetes. Some Imidazoline compounds also bind a-adrenergic receptors, however S43126 is a selective agonist to the I1 -imidazoline receptor. Our general hypothesis states that imidazoline compounds exert metabolic effects by activation of PC-PLC and stimulation of glucose uptake. This hypothesis will be tested by two specific aims. (1) Imidazoline receptors are coupled to PC-PLC pathways and blood pressure reduction in vivo and (2) Imidazoline receptor activation is coupled to an increased uptake of glucose via the PI3K dependent pathway. Results obtained from this proposal will not only lead to an understanding of how a single compound can act to positively impact both hypertension and hyperglycemia but also advance imidazoline research and stimulate the development of these agents for therapeutic use in the United States. Furthermore, this project provides an excellent training environment for undergraduate and graduate students including underrepresented minorities. PUBLIC HEALTH RELEVANCE: Type 2 diabetes affects millions of people worldwide leading to a worsening of periodontal disease, renal failure, cardiovascular problems, retinopathy and neuropathy. Many diabetics also need medications for hypertension, and compliance becomes an issue with multiple medications. Novel imidazoline compounds offer the possibility of treating diabetes and hypertension with a single medication, thereby improving compliance and ultimately patient health.